Nicotine, the active ingredient in tobacco, stimulates neuronal receptors by triggering the release of neurotransmitters such as dopamine and acetylcholine. To produce this effect, nicotine is believed to bind to one or more of a family of receptors known as nicotinic acetylcholine receptors (nAChRs).
Tobacco use is widely recognized as damaging to the health of individual users and draining on public resources. Although many addicted smokers desire to quit, dependency on the artificially high levels of neurotransmitters caused by nicotine can make smoking cessation a very difficult process. Discontinuing the intake of nicotine leads to sometimes severe physical and psychological withdrawal symptoms that may include cravings, irritability, nervousness, sleep deprivation, weight gain, and physical illness.
Therapeutic approaches to aid in smoking cessation include nicotine replacement therapy (NRT) methodologies that involve the slow delivery of controlled doses of nicotine. For the addicted smoker, maintaining a low level of nicotine in the circulation helps to address the physical and psychological withdrawal symptoms associated with smoking cessation. However, the efficacy of NRT methods is often very low.
Non-nicotine based methods of aiding smoking cessation that are under investigation include the use of anti-depressants and weight-reducing medications. Coc et al., (2005) J. Med Chem. 48, 3474 describes the synthesis of an azepine derivative that, like nicotine, binds to one of the nAChRs. It is hypothesized that a therapeutic agent that competitively binds to nAChRs, precluding the binding of nicotine, would thereby limit or eliminate the satisfaction that smoking provides.
Various compounds and methods have been investigated as aids for smoking cessation. For example, U.S. Pat. No. 6,964,972 describes 8-azabicylco[3.2.1]oct-2-ene and -octane derivatives which are useful for the treatment of a range of diseases or conditions or disorders characterized by decreased cholinergic function or responsive to the activity of nicotinic ACh receptor modulators.
U.S. Pat. No. 6,541,478 describes a method for treating a person for nicotine dependency by administering an opioid antagonist such as naltrexone.
U.S. Pat. No. 6,495,605 describes methods and compositions that utilize the optically pure (+)-isomer of bupropion to assist in smoking cessation, and for treating smoking and nicotine addiction.
In addition, various nAChRs have been identified as targets for drugs that aid in smoking cessation. For example, U.S. Pat. Nos. 6,951,868, 6,919,359, 6,911,543, 6,894,042, 6,858,613, 6,852,716, and 6,849620 are directed towards azabicyclic compounds that are useful in pharmaceuticals in which the α7 nAChR is known to be involved.
However, it is not well understood which of the numerous nAChRs is/are most relevant for smoking cessation. Development of competitive ligands for binding to nAChRs remains a promising area of research, and there remains a need in the art for improved therapeutic approaches to aid in smoking cessation.
Furthermore, nAChRs play an important role in regulating CNS and other physiological functions by mediating the endogenous neurotransmitter, acetylcholine. Consequently, a wide variety of conditions are associated with nAChRs and the chemicals with which they interact. Effective approaches toward treating any or all of these conditions may be achieved via drugs that target the function of nAChRs. For example, and in addition to nicotine addiction, nAChRs are associated with medical conditions such as learning disorders, eating disorders, Alzheimer's disease and other memory-impairing conditions, Parkinsons disease, and addictions to drugs such as opiates and cocaine. As with nicotine addiction, there remains a need in the art for improved therapeutic approaches to these nAChR-associated conditions.
An improved therapeutic approach to aid in the treatment of drug addictions (such as nicotine) or other medical conditions involving nAChRs might involve a compound that: (1) has a selective and high binding affinity for one or more subtype of neuronal nAChR; (2) has a low binding affinity for muscular AChRs; (3) has low toxicity in vivo; and (4) can be administered to the patient effectively and via one or more of a variety of methods.
It is an object of the present disclosure to address one or more of the aforementioned needs in the art, by providing compounds, compositions, methods of use, and methods of treatment that are directed at modulating one or more nAChR.